Fiche publication
Date publication
août 2018
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GALZI Jean-Luc
,
Pr HAIECH Jacques
,
Pr HIBERT Marcel
,
Dr VILLA Pascal
Tous les auteurs :
Regenass P, Abboud D, Daubeuf F, Lehalle C, Gizzi P, Riché S, Hachet-Haas M, Rohmer F, Gasparik V, Boeglin D, Haiech J, Knehans T, Rognan D, Heissler D, Marsol C, Villa P, Galzi JL, Hibert M, Frossard N, Bonnet D
Lien Pubmed
Résumé
We previously reported small molecules that bind the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralize its biological activity. These neutraligands encompass a chalcone chemotype, and suffer from limitations such as poor chemical stability, solubility and oral activity. Herein, we report a systematic structure-activity relationship study around the first neutraligand of CXCL12, Chalcone 4 (1) resulting in the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1. In addition, 57 is no longer Michael acceptor. Both 1 and 57 reduce eosinophil recruitment in a murine model of allergic airway hypereosinophilia. Yet, 57 is the only one to display inhibitory activity following oral administration. Thereby, we here describe 57 as the first orally active CXCL12 neutraligand with anti-inflammatory properties. Combined with a high binding selectivity for CXCL12 over other chemokines, 57 represents a powerful pharmacological tool to investigate CXCL12 physiology in vivo, and to explore the activity of chemokine neutralization in inflammatory and related diseases.
Référence
J. Med. Chem.. 2018 Aug 14;:
